Clinical studies provide strong evidence that behavioral and psychosocial factors, including stressful life experiences, are associated with altered immune function and susceptibility to opportunistic infection. Since stress is a risk factor for human disease the neurochemical and immunological consequences and the mechanism by which immunosupression is brought is an important area of study. Initiation of substance abuse, has been linked to emotional distress and stressful lifestyles. Alcohol abuse and alcohol related mortality are both prevalent among individuals that are exposed to greater number of psychological and physical stressors. The biological effectors mediating stress response is the hypothalamic pituitary adrenal axis that regulate the release of adrenocorticortropin (ACTH), beta endorphin and cortisol. Our preliminary data show that restraint stress mediated decrease in Th1 cytokines (Il-2 and IFNg) and increase in Th2 (Il-4 and IL 5) cytokines are significantly inhibited in mu-opioid receptor knock out mice. We further show that in vitro chronic treatment of splenocytes from wild type mice with beta endorphin results in Th2 differentiation. This effect was significantly attenuated in splenocytes harvested from Mu-opioid receptor knockout mice (MORKO). The central hypothesis in this proposal is that beta endorphin induced immunosupression in restraint stress is mediated by the mu-opioid receptor. The aims of this proposal will investigate, in a chronic stress model, the role of beta endorphin and the mechanisms by which mu-opioid receptor mediates stress induced immunosupression. Understanding the mechanism/s by which stress/beta endorphin modulate the Th1/Th2 balance would be extremely helpful in designing therapeutic approaches in clinical situations where preferential redirection to a specific Th phenotype can be beneficial.